Development of Emergent PET Tracers in Frontotemporal Lobar Degeneration

项目摘要/摘要 这是David Soleimani-Meigooni博士的K23职业发展奖申请，他是一名行为主义者 神经学家和临床讲师，正在确立自己作为加州大学初级研究员的地位 加州旧金山(加州大学旧金山分校)记忆和衰老中心(MAC)。他的长期目标是成为一名 临床医生-科学家，将领导一个独立的研究计划，以推进临床前 用于神经退行性疾病诊断和监测的新型PET示踪剂的开发/翻译 与额颞叶变性(FTLD)病理有关。通过K23和最佳培训 在环境和资源方面，Soleimani-Meigooni博士的目标是实现以下培训目标：1. 精通PET图像采集的药代动力学放射性示踪剂建模和优化。2.至 精通PET定量分析。3.学习定量神经病理学技术。4.为了获得 研究设计和生物统计学方面的高级技能。5.掌握临床研究操作、研究技能 道德和仁慈精神。6.将他的K23培训和发现落实到R01中，使他能够 成为参与新型PET示踪剂临床前开发/翻译的独立调查者 FTLD。为了实现这些培训目标，Soleimani-Meigooni博士组建了一支世界级的导师团队 包括主要导师吉尔·拉比诺维奇博士，他是行为神经学家和PET神经成像领域的领导者 神经退行性疾病；共同导师，威廉·贾格斯特博士，行为神经学家和技术专家 PET成像方面，包括放射性示踪剂开发和药代动力学建模；共同导师，Lea博士 格林伯格是一位神经病理学家，加州大学旧金山分校神经退行性疾病脑库的联合负责人，也是 FTLD和定量神经病理测量；合作者苏珊娜·贝克博士，一位技术 在PET成像方面的专业知识；以及合作者，生物统计学家伊莎贝尔·伊莱恩·艾伦博士。 该项目将评估/验证新的PET示踪剂，以帮助诊断和监测FTLD。侯选人 PET示踪剂包括一种与非阿尔茨海默病tau蛋白结合的新型配体[18F]PI-2620，以及另一种配体 它与突触结合，[18F]SynVesT-1。还需要进一步评估以确定[18F]PI-2620是否可以 区分FTLD伴Tau病理(FTLD-tau)和FTLD伴TDP-43病理(FTLD-TDP)，如果 [18F]SynVesT-1是FTLD突触丢失和疾病状态的敏感标志物。在这个项目中，两种示踪剂 将通过比较FTLD-tau和FTLD-TDP患者的示踪剂滞留模式来评估/验证 和其他神经退行性疾病(目标1)；将区域示踪剂滞留与临床措施和 脑部结构磁共振改变(皮质厚度或皮质下体积减少)(目标2)； PET与病理的定量相关性(目标3)。该项目提供的关键数据可以支持 这些放射性示踪剂的临床应用和作为临床试验生物标记物的翻译。

PROJECT SUMMARY/ABSTRACT This is a K23 career development award application for Dr. David Soleimani-Meigooni, a behavioral neurologist and Clinical Instructor who is establishing himself as a junior investigator at the University of California, San Francisco (UCSF) Memory and Aging Center (MAC). His long-term goal is to become a clinician-scientist who will lead an independent research program to advance the pre-clinical development/translation of novel PET tracers for diagnosis and monitoring of neurodegenerative diseases associated with frontotemporal lobar degeneration (FTLD) pathology. Through the K23 and the optimal training environment and resources of the MAC, Dr. Soleimani-Meigooni aims to achieve these training goals: 1. To become proficient in pharmacokinetic radiotracer modeling and optimization of PET image acquisition. 2. To become proficient in quantitative PET analyses. 3. To learn quantitative neuropathology techniques. 4. To gain advanced skills in study design and biostatistics. 5. To gain skills in clinical research operations, research ethics, and grantsmanship. 6. To implement his K23 training and findings into an R01 that will allow him to become an independent investigator involved in pre-clinical development/translation of novel PET tracers for FTLD. To achieve these training goals, Dr. Soleimani-Meigooni has assembled a world-class mentorship team including primary mentor, Dr. Gil Rabinovici, a behavioral neurologist and leader in PET neuroimaging of neurodegenerative diseases; co-mentor, Dr. William Jagust, a behavioral neurologist and expert in technical aspects of PET imaging, including radiotracer development and pharmacokinetic modeling; co-mentor, Dr. Lea Grinberg, a neuropathologist, co-leader of the UCSF Neurodegenerative Disease Brain Bank, and expert on FTLD and quantitative neuropathological measures; collaborator, Dr. Suzanne Baker, a scientist with technical expertise in PET imaging; and, collaborator, Dr. Isabel Elaine Allen, an expert biostatistician. This project will evaluate/validate new PET tracers to aid in diagnosis and monitoring of FTLD. Candidate PET tracers include a novel ligand that binds to non-Alzheimer tau proteins, [18F]PI-2620, and another ligand that binds to synapses, [18F]SynVesT-1. Further evaluation is needed to determine if [18F]PI-2620 can distinguish FTLD with tau pathology (FTLD-tau) from FTLD with TDP-43 pathology (FTLD-TDP), and if [18F]SynVesT-1 is a sensitive marker of synapse loss and disease state in FTLD. In this project, both tracers will be evaluated/validated by comparing patterns of tracer retention in patients with FTLD-tau to FTLD-TDP and other neurodegenerative diseases (Aim 1); correlating regional tracer retention to clinical measures and structural brain MRI changes (loss of cortical thickness or subcortical volume) (Aim 2); and performing quantitative PET-to-pathology correlations (Aim 3). This project provides critical data that could support the translation of these radiotracers for clinical use and application as clinical trial biomarkers.